Alexandra Huber

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B6 Reprogramming of macrophages by the mycobacterial cord factor

Principal investigator
Roland Lang

Mentor
Anja Lührmann

Reprogramming of macrophages by the mycobacterial cord factor

Mycobacterium tuberculosis (Mtb) is the causal agent of tuberculosis, a fatal disease that causes almost 2 million deaths a year. The bacterium has developed specific intracellular survival mechanisms, circumventing host defense through bacterial effectors. Understanding the molecular mechanisms of these survival strategies may prove useful for prevention and treatment approaches.
The mycobacterial cord factor plays a major role in the bacterium's virulence. It was identified in the 1950s as the glycolipid trehalose-6,6-dimycolate (TDM), the most abundant component of the mycobacterial cell wall. We and others identified the macrophage-inducible C-type lectin Mincle as the host receptor for TDM signaling via Syk-Card9. The cord factor plays in fact two roles in the infection process: on the one hand, TDM is a pathogen-associated molecular pattern (PAMP) that is recognized by the host and triggers defense reactions. On the other hand, TDM is a key factor for intracellular survival of the bacterium, thus making it a bacterial effector as well (Figure). Inhibition of phagosome maturation is achieved by the cord factor itself, as well as a reduction of costimulatory molecules and cytokines.
The central aim of this work is to define the effector functions of TDM in murine macrophages. We hypothesize that TDM exploits the very pathway that is needed for its recognition as a PAMP. Therefore, we focus our experiments on possible exploitation of Mincle and its Syk-Card9 downstream-signaling pathway by the mycobacterial cord factor for reprogramming of macrophages.

Figure: Diverse effects of the mycobacterial cord factor TDM. Left: TDM acts as a PAMP for the host cell. Recognition via Mincle activates macrophages, induces the formation of granulomas and has an adjuvant effect on the organism. Right: The effector functions of TDM include the inhibition of phagosome maturation as well as the reduction of costimulatory molecules and cytokines.

 

Publications

Huber A., Kallerup RS., Korsholm KS., Franzyk H., Lepenies B., Christiensen D., Foged C. and Lang R. (2016).  Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, 1 activation of macrophages in vitro, and adjuvant activity in vivo. Innate Immunity 0(0): 1-14

Schoenen H., Huber A., Sonda N., Zimmermann S., Jantsch J., Lepenies B., Bronte V. and Lang R. (2014). Differential Control of Mincle-Dependent Cord Factor Recognition and Macrophage Responses by the Transcription Factors C/EBPβ and HIF1α. J Immunol 193(7): 3664-3675

 

Presentations

October 2015 2nd International SFB796 Conference, Erlangen, Germany
”Reprogramming of murine macrophages by the mycobacterial cord factor”
Poster
     
September 2015 67. Jahrestagung der Deutschen Gesellschaft für Hygiene und Mikrobiolgie, DGHM, Münster, Germany
”The mycobacterial cord factor TDM: dual role in cross-regulation of IFNγ responses”
Talk
     
July 2015 7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
”The mycobacterial cord factor TDM: dual role in cross-regulation of IFNγ responses”
Talk
     
March 2015

19th Minisymposium "Infection and Immunity", Rothenfels Castle, Germany
“Repression of IFNgamma-mediated responses by the mycobacterial cord factor”

Talk
     
October 2014 28th Annual Conference of the European Macrophage and Dendritic Cell Society (EMDS), Vienna, Austria. "Transcriptional profiling of cord-factor-stimulated macrophages reveals synergy and antagonism withTLR-/IFNγ-induced responses"
Poster
     
July 2014 6th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
“Transcriptional profiling reveals Cord-factor-mediated antagonism of IFNg-induced responses in murine macrophages”
Talk
     
September 2013 65. Jahrestagung der Deutschen Gesellschaft für Hygiene und Mikrobiologie / Jahrestagung der Deutschen Gesellschaft für Infektionsbiologie, Rostock, Germany
Impairment of MHCII expression by the mycobacterial cord factor
Talk
     
July 2013 5th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Reprogramming of murine macrophages by the mycobacterial cord factor
Talk